tbuckley/cabot-search huggingface dataset:
Abstract 1440: Identifying inherited genetic variation that impacts individuals’ ability to metabolize arsenic and susceptibility to toxicity
Authors: Lizeth I. Tamayo, Lin Tong, Muhammad G. Kibriya, Farzana Jasmine, Habibul Ahsan, Brandon L. Pierce
Journal: Cancer Research (2022)

Abstract Inorganic arsenic (iAs) is a class I human carcinogen, and exposure to iAs affects &amp;gt;200 million individuals worldwide. In Bangladesh, &amp;gt;57 million individuals are chronically exposed to iAs through drinking-water. There is inter-individual variation in arsenic metabolism efficiency (AME) due to inherited genetic variation, and this variability impacts individuals’ internal dose of arsenic and their susceptibility to toxicity. Identifying genetic determinants of AME to help identify individuals at higher risk for toxicity has been a focus within genetic epidemiology research. Consumed arsenic enters the blood in as iAs. Sequential reduction and methylation reactions are catalyzed by glutathione and arsenic methyltransferase (AS3MT) respectively, producing monomethylated (MMA) and dimethylated (DMA) forms of arsenic. Generation of DMA is beneficial because DMA is more easily expelled from the body in urine compared to MMA or iAs. AME is often represented by the percent of the arsenic species in urine that exists as DMA. Previous studies have identified genetic variants in the AS3MT (10q24.32) and FTCD (21q22.3) regions as showing clear association with AME. However, additional regions containing variants showing robust and replicable association with AME have not yet been identified, although studies of AME heritability suggest that additional variants are likely to exist. We used data from &amp;gt;7,000 participants from two studies of Bangladesh individuals with varying levels of exposure to arsenic through drinking water (The Health Effects of Arsenic Longitudinal Study, HEALS, and the Bangladesh Vitamin E and Selenium Trial, BEST) to identify genetic variation that impacts individuals’ ability to metabolize arsenic and their susceptibility to toxicity (i.e., arsenic-induced skin lesions). Our preliminary results suggest novel associations with AME in the 1q24.3 region (p= 5.16 x10-14) and with skin lesion risk in the 6p21.33 region (p=1.37x10-9). The identified variants in the 1q24.3 region reside in and around the FMO3 gene. FMOs are enzymes involved in xenobiotic metabolism; therefore, it is plausible that they may play a role in arsenic metabolism. The 6p21.33 signal is in the major histocompatibility complex (MHC) region, which contains numerous key immune response genes (e.g., HLA genes). These results suggest the existence of additional variants associated with AME and arsenic toxicity risk. Citation Format: Lizeth I. Tamayo, Lin Tong, Muhammad G. Kibriya, Farzana Jasmine, Habibul Ahsan, Brandon L. Pierce. Identifying inherited genetic variation that impacts individuals’ ability to metabolize arsenic and susceptibility to toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1440.
Abstract 5311: Auranofin sensitizes paclitaxel induced apoptotic cell death through oxidative mechanism in breast cancer cells
Authors: N. Rajendra Prasad, Deepika Natarajan
Journal: Cancer Research (2022)

Abstract Breast cancer cells exhibit several basal redox systems, thus poorly responding to oxidative cell death. These intrinsic redox statuses capitalize on the efficacy of chemotherapeutic drugs. Auranofin, an FDA-approved gold compound documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel sensitizing effect of auranofin by targeting redox balance in the MDA-MB-231 and MCF-7 breast cancer cell lines. We observed that auranofin inhibits thioredoxin reductase activity (TrxR) in these breast cancer cells and collapses the cellular antioxidants status, including the reduced activities of superoxide dismutase, catalase, and glutathione peroxidase. Furthermore, it has been noticed that auranofin augmented paclitaxel mediated cytotoxicity in a concentration dependant manner in both the MDA-MB-231 and MCF-7 cell lines. Furthermore, auranofin increased intracellular ROS levels (DCFH-DA staining) and altered mitochondrial membrane potential (Rhodamine-123 staining) in these breast cancer cell lines. The proapoptotic markers such as p53, Bax, and caspase-3 and caspase-9 expressions were higher in auranofin plus paclitaxel treated breast cancer cells when compared to paclitaxel alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA-MB-231 and MCF-7 breast cancer cell lines. Citation Format: N. Rajendra Prasad, Deepika Natarajan. Auranofin sensitizes paclitaxel induced apoptotic cell death through oxidative mechanism in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5311.
Abstract 6197: The role of the integrated stress response in pancreatic cancer adaptation to tumor microenvironmental nutrient stress
Authors: Chufan Cai
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate ~10%1. PDAC is characterized by an altered/abnormal nutrient tumormicroenvironment (TME)2, and cancer cells must adapt metabolically, which exposes potentialtherapeutic targetable vulnerabilities. Therefore, we seek to identify metabolic pathways thatallow PDAC adaptation to such abnormal TME. The integrated stress response (ISR) is anintracellular stress response pathway that senses diverse stressors, and subsequently initiatesdownstream stress adaptations3. We find both murine and human PDAC have elevatedexpression of ATF4, the most well-characterized ISR effector, compared to paired healthypancreas by immunohistochemistry staining. Further, I find the ISR is activated and critical forPDAC survival/proliferation upon physiological PDAC TME nutrient stress. What is triggering theISR activation in PDAC? Through a variety of studies, I determined that it was the amino acidstress, specifically the depletion of arginine and asparagine, that activated the ISR upstreamkinase GCN2, which is responsible for ATF4 upregulation upon PDAC TME nutritional stress.Through CRISPR-based competition assays, I determined that ATF4 activity was critical forPDAC cells to cope with the depletion of arginine and asparagine, and ATF4 activity wasdispensable when these two amino acids were supplied even though cultured in PDACphysiological TME conditions. Currently, I am seeking to validate these findings in murine PDACmodels, and to determine if ATF4 or GCN2 could be relevant therapeutic targets, using an invivo tumor competition assay that I am developing. Altogether, I find the ISR is active in PDACboth ex vivo and in vivo, and suggest that the ISR is critical for PDAC survival/proliferation byallowing adaptation to abnormal PDAC amino acid TME. This work suggests that the ISR is anovel therapeutic target for PDAC treatment, which ultimately can benefit PDAC patients. References: 1. Cancer Facts &amp; Figures 2021. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2021.html. 2. Sullivan, M. R. et al. Quantification of microenvironmental metabolites in murine cancersreveals determinants of tumor nutrient availability. Elife 8, (2019).3. Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374-1395(2016). Citation Format: Chufan Cai. The role of the integrated stress response in pancreatic cancer adaptation to tumor microenvironmental nutrient stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6197.
Abstract 1483: RNA interference seed-based approach to inhibit androgen signaling and induce prostate cancer cell death
Authors: Joshua M. Corbin, Maria J. Ruiz-Echevarria
Journal: Cancer Research (2022)

Abstract The goal of this study is to identify RNA interference (RNAi) seed sequences that inhibit androgen signaling and induce toxicity in prostate cancer (PCa) cells. The high prevalence of acquired resistance to androgen deprivation therapy, as well as first and second generation androgen receptor (AR) antagonists, drives the development of lethal castration resistant prostate cancer (CRPC). As a result, PCa remains one of the leading causes of cancer related deaths in men. AR amplification, gain of function mutations and constitutively active splice isoforms of the AR, and the overexpression of AR coregulators, play considerable roles in promoting CRPC by sustaining AR activity in the presence of the low androgen environment and/or AR antagonists. The development of specific small molecule inhibitors of AR splice isoforms has been largely unsuccessful, and inhibitors of individual AR coregulators have not translated well into the clinic, likely due to their large number and functional redundancies. Therefore, novel therapeutic strategies for targeting androgen signaling in CRPC are necessary. Previous studies in our lab have demonstrated RNAi-mediated PCa cell death through seed region (nucleotides 2-8) complementarity of shRNA/siRNA guide strands to the 3’UTR of the AR and multiple AR coregulators and essential genes. In the current study, we used an unbiased novel seed-based shRNA screen to identify seed sequences that are toxic to different PCa cells, including CRPC cells expressing the clinically relevant constitutively active AR variant 7 (AR-V7). Common motifs were identified among toxic seed sequences, and the miRDB target prediction database was used to select those seeds that were predicted to target the AR and AR coregulators. Using RNA-seq analyses we confirmed that selected seed sequences inhibited global androgen signaling and identified potential direct targets known to be relevant to PCa. Conclusions: These studies have identified androgen signaling inhibitory sequences that have the potential to be used in RNAi-seed based therapies for PCa. The ability to inhibit the expression of the AR and multiple essential AR coregulators simultaneously with one agent, and the reduced likelihood of developed resistance, are considerable benefits of this approach. Citation Format: Joshua M. Corbin, Maria J. Ruiz-Echevarria. RNA interference seed-based approach to inhibit androgen signaling and induce prostate cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1483.
Abstract LB077: Reengineering ponatinib to minimize cardiovascular toxicity
Authors: Anna Pavlovna Hnatiuk, Arne A. Bruyneel, Dhanir Taylor, Mallesh Pandrala, Arpit Dheeraj, Wendy Li, Ricardo Serrano Fernandez, Dries A. Feyen, Michelle M. Wu, Prashila Amatya, Isabel Morgado, Volker Wiebking, Matthew H. Porteus, Sanjay Malhotra, Mark Mercola
Journal: Cancer Research (2022)

Abstract Introduction and Purpose of the Study: The advent of small molecule Tyrosine Kinase Inhibitors (TKIs) has revolutionized cancer treatment and greatly improved patient survival. However, the life-threatening cardiovascular toxicity of many TKIs present major concerns. Ponatinib is the most effective treatment for patients harboring the common T315I mutation of BCR-ABL that drives Chronic Myeloid Leukemia (CML) yet is one of the most cardiotoxic of TKIs. Ponatinib-induced events include myocardial infarction, heart failure, stroke, peripheral vascular disease and venous thrombosis. The aim of this study is to reengineer the chemical structure of ponatinib to minimize its adverse cardiovascular effects by using in vitro and in vivo models of cardiovascular toxicity. Experimental Procedures: We developed in vitro cardiovascular toxicity assays using human iPSC-cardiomyocytes (hiPSC-CMs) and human microvascular endothelial cells (HMVECs), and assessed anti-tumor efficacy in T315I mutated K562 CML cells. The cardiotoxicity was determined by impairment of cardiomyocyte contractility function, the vascular toxicity was defined by inability to form capillary-like networks in vasculogenesis assays. In vitro screening of ponatinib analogues probed chemical moieties responsible for its cardiovascular toxicity that were confirmed using mice xenograft mice models with human T315I mutant K562 cells. Summary of Unpublished Data: Compared to ponatinib, refined analogues showed markedly decreased adverse effects on HMVECs vasculogenesis and hiPSC-CMs contractility in vitro. The therapeutic window was increased in vivo, leading to regression of human T315I mutant CML xenografts comparable to ponatinib but without increasing serum levels of cardiac troponin. The kinase inhibition profiles of the “safe” analogues compared to ponatinib identified candidate mediators of ponatinib-induced toxicity. Validation by selective knockdown revealed likely mediators of cardiotoxicity, including FGFR. Conclusions: We succeeded in engineering a cardiovascular safe TKI that retained effective therapeutic properties against BCR-ABL T351 mutated form of CML, but with substantially decreased cardiovascular toxicity. Citation Format: Anna Pavlovna Hnatiuk, Arne A. Bruyneel, Dhanir Taylor, Mallesh Pandrala, Arpit Dheeraj, Wendy Li, Ricardo Serrano Fernandez, Dries A. Feyen, Michelle M. Wu, Prashila Amatya, Isabel Morgado, Volker Wiebking, Matthew H. Porteus, Sanjay Malhotra, Mark Mercola. Reengineering ponatinib to minimize cardiovascular toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB077.
Abstract 1519: ALDH1A1 enhances micro homology-mediated end joining by increasing POLQ expression
Authors: Kousalya Lavudi, Ananya Banerjee, Shurui Cai, Na Li, Xuetao Bai, Wang Qi-En
Journal: Cancer Research (2022)

Abstract Aldehyde dehydrogenase (ALDH) is a superfamily of 19 known enzymes that participated in the metabolism of endogenous and exogenous aldehydes. ALDH1A1 is a major subtype contributing to high ALDH activity out of all ALDH isoforms and plays a critical role in the maintenance of cancer stem cells. Our previous studies have shown that ALDH1A1 is able to reduce the sensitivity of BRCA2-/- ovarian cancer cells to PARP inhibitors by enhancing microhomology-mediated end joining (MMEJ). MMEJ uses 5-25 base pair micro homologous sequences to align the broken strands before joining, and this repair pathway requires DNA polymerase θ (Pol θ, encoded by POLQ). Here we show that ALDH1A1 can increase the expression of Pol θ, at both mRNA and protein levels, in ovarian cancer cell lines. ALDH1A1 is reported to catalyze the production of all-trans retinoic acid (ATRA), which can bind to the retinoic acid receptor (RAR), and promote transcription of the downstream target genes that possess retinoic acid response element (RARE) in their promoter regions. Interestingly we identified several RAREs in the promoter region of the POLQ gene. Thus, we hypothesized that ALDH1A1 promotes Pol θ expression via activation of the RAR signaling pathway. We found that ATRA and RAR agonist (CH55) increased but pan RAR antagonist (AGN193109) treatment decreased the expression of POLQ, indicating that the RAR pathway is involved in the transcription of POLQ. We also demonstrated that RARα can bind to the promoter region of Pol Q, activation of RAR signaling by treatment with ATRA or CH55 increased the enrichment of K27 acetylated histone H3 in this promoter region. Moreover, we showed that mutated ALDH1A1 lacking the enzyme activity was unable to enhance POLQ transcription. These data suggest that ALDH1A1 enhances the Pol Q expression by increasing the production of ATRA which further activates the RAR signaling pathway. Citation Format: Kousalya Lavudi, Ananya Banerjee, Shurui Cai, Na Li, Xuetao Bai, Wang Qi-En. ALDH1A1 enhances micro homology-mediated end joining by increasing POLQ expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1519.
Abstract 5838: The landscape of EGFR exon 20 insertion mutations in Chinese patients with non-small cell lung cancer
Authors: shun xu, Zhichao Fu
Journal: Cancer Research (2022)

Abstract Background: The epidermal growth factor receptor (EGFR) is one of the most commonly altered genes in non-small cell lung cancer(NSCLC). Of these, insertion mutation in 20 exon (Ex20ins) of the EGFR occurs less frequently. In comparison with the common EGFR mutations (19Del/L858R), the NSCLC patients with Ex20ins have a worse prognosis. Recently, the FDA approved targeted oral therapeutic agent for NSCLC patients with EX20ins mutation, which has markedly improved their survival. Here we carry out a complete analysis of the frequency and types of EGFR 20 Exon insertion mutations in the large-scale NSCLC cohort of the Chinese population. Methods: From January 2020 to October 2021, a total of 4,091 patients were confirmed as NSCLC were included in the study. The Next-generation sequencing was utilized for detecting genetic mutations. Results: Among the 4,091 NSCLC patients, 2,411 (58.9%) experienced EGFR mutations. In which we identified 90 patients(2.2%) with Ex20ins. All of the Ex20ins were localized between amino acids S767-V774, and after C-helix of the EGFR kinase domain. Different from the exon 19 deletion, we found that Ex20ins exhibits various types of mutations. A total of 34 Ex20ins types were detected, with the most common A767_V769dupASV and S768_D770dupSVD mutations, accounting for 26% and 22.2% respectively. In addition, H773dupH (6.67%), H773_V774dupHV(5.56%), H773_V774insAH (2.22%), D770_N771insG (2.22%), and N771_P772insG(2.22%) were also observed in the NSCLC patients. Conclusions: We described the landscape of EGFR Ex20ins in Chinese NSCLC patients cohort. Based on the large sample size, the frequency of the Ex20ins mutation in Chinese NSCLC patients was 2.2%, and the types of EGFR Ex20ins mutation were highly heterogeneous. Citation Format: shun xu, Zhichao Fu. The landscape of EGFR exon 20 insertion mutations in Chinese patients with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5838.
Abstract 1185: Survey of genomic alterations in Merkel cell carcinoma (MCC) in the AACR Project Genie real-world database
Authors: Danielle Brazel, Priyanka Kumar, Hung Doan, Justin T. Moyers
Journal: Cancer Research (2022)

Abstract Introduction: MCC is a rare and highly aggressive cutaneous neuroendocrine carcinoma with increasing incidence over the last few decades. Cytotoxic chemotherapy and checkpoint inhibitors have provided modest treatment options, however, there are no approved or standard of care targeted treatment options. Here we surveyed the presence of targetable alterations in the AACR Project Genie Database Methods: Individual patient data were accessed from the cBioPortal. Variables of interest include demographic data, alterations annotated by OncoKB therapeutic evidence level, and TCGA PanCancer pathway alterations. Results: A total of 295 patients with MCC were cataloged in the database. Patients included were 34.6% (n=102) female with a median age of 71. Patients identified race as 91.2% (n=269) white, 2.4% (n=7) African American, and 0.4% (n=2) Asian. The median number of alterations was 3.00 (SD 21.4, Range 0-178). Oncogenic alterations represented 17.4% (n=660 of 3799) of mutations. Sampled tissue originated from primary tumor in 54% (n=161) verses metastases in 42.4% (n=125). NGS identified 18.5% (n=55) with an FDA approved drug for use in a biomarker approved indication or approved drug in another indication (Level 1-3). An additional 13.9% (n=41) had a Level 4 (L4) mutation. The most common Level 3B gene mutations include PIK3CA (4.1%, n=12), and BRCA1/2 (4.1%, n=12), HRAS (1.7%, n=5), TSC1/2 (1.7%, n=5). The most common L4 mutations include PTEN (4.4%, n=13), ARID1A (3.7%, n=11), and CDKN2A (2.4%, n=7). Only three fusions were identified; L3B fusions ATM-CDK12 and TSC2 along with Level 4 PTEN. Copy number alterations were identified in a small subset of patients. L3B CNAs include ATM, CHEK1 (n=1), BARD1 (n=1), BRCA2 (n=1), RAD51B (n=1), RAD51D (n=1). Level 4 CNAs identified CDKN2A (n=4) and PTEN (n=1). In 60.7% cases, PanCancer pathways were altered and 28.5% had alterations in multiple pathways. The most commonly altered pathways were RTK-RAS (37.6%, n=111), TP53 (33.9%, n=100), Cell Cycle (33.9, n=100), PI3K (32.2%, n=95) and NOTCH (30.8%, n=91). Additionally, oncogenic DNA damage repair gene alterations (BRCA1/2, CHEK1/2, ATM, PALB2, BRIP1, RAD51) were present in 7.5% (n=22) of cases. Conclusions: Here we identified a subset of patients with targetable mutations in MCC. The majority of patients had oncogenic alterations in cancer pathways which may support the investigation of kinase inhibitors as single agent or in combination with immunotherapy or cytotoxic chemotherapy in Merkel Cell Carcinoma. Citation Format: Danielle Brazel, Priyanka Kumar, Hung Doan, Justin T. Moyers. Survey of genomic alterations in Merkel cell carcinoma (MCC) in the AACR Project Genie real-world database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1185.